2. Academic Validation
  3. Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor

Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor

  • ACS Med Chem Lett. 2020 Apr 23;11(6):1324-1329. doi: 10.1021/acsmedchemlett.0c00155.
Jonathan E Wilson 1,  Gaurav Patel 2,  Chirag Patel 2,  Francois Brucelle 1,  Annissa Huhn 1,  Anna S Gardberg 1,  Florence Poy 1,  Nico Cantone 1,  Archana Bommi-Reddy 1,  Robert J Sims 3rd 1,  Richard T Cummings 1,  Julian R Levell 1
Affiliations

Affiliations

  • 1 Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
  • 2 Piramal Enterprises Limited-Discovery Solutions, Ahmedabad, Gujarat 382 213, India.
PMID: 32551019 DOI: 10.1021/acsmedchemlett.0c00155
Abstract

The histone acetyltransferases, CREB binding protein (CBP) and EP300, are master transcriptional co-regulators that have been implicated in numerous diseases, such as Cancer, inflammatory disorders, and neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP Histone Acetyltransferase (HAT) inhibitor, CPI-1612 or 17, was developed from the lead compound 3. Replacement of the indole scaffold of 3 with the aminopyridine scaffold of 17 led to improvements in potency, solubility, and bioavailability. These characteristics resulted in a 20-fold lower efficacious dose for 17 relative to lead 3 in a JEKO-1 tumor mouse xenograft study.

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